The pituitary glands from obese mice (ob/ob), from mice rendered obese with gold-thioglucose and by dietary manipulation, and from lean mice given a glucose load or following excessive feeding, secrete a factor which stimulates the release of insulin from isolated mouse pancreatic islets. Evidence has been obtained suggesting that the pituitary insulin sucretagogue, which is located in the neuro-intermediate lobe of the gland, is the corticotrophin-like intermediate lobe peptide CLIP, corresponding to the 18-39 fragment of ACTH. Experiments with pure CLIP and related compounds are in progress. Perifusates of the neuro-intermediate pituitary lobe of mice rapidly stimulate insulin secretion in the perfused rat pancreas. Quantitative studies are being undertaken to compare the obese and lean mice. Studies on isolated islets with perifusates of pituitary glands from ob/ob and lean ob/plus and plus/plus have demonstrated a gene dosage response. The biosynthesis of the neuro-intermediate lobe peptides is being investigated by incubating the tissue with 14C proline and separating the peptide in an extract on biogel chromatography columns. The radioactivity of the peptides and their cross-reactivity with specific ACTH C- and N- terminal antisera are measured. Specific activity of the fractions from obese and lean mice are being compared. The insulin releasing properties of the fractionated peptides will be measured on islets and in the perfused pancreas.